1. Field of the Invention
The present invention relates to a prolonged release dosage form of a drug and a method for producing the same.
2. Related Art Statement
A prolonged release dosage form of a drug is a dosage form designed so that a medicinal agent is released or dissolved gradually within a body. There are many kinds of methods for controlling the dissolution of a medicinal agent by prolonged release. Among them, the usual method is one wherein a coating layer is provided on the surface of a granule or a tablet containing a medicinal agent to control the release of the medicinal agent, or one wherein a medicinal agent is dispersed in wax or a water insoluble matrix to control its release.
In the prolonged release dosage forms in which the release of a medicinal agent is controlled by the coating layer, a medicinal agent is first formed in granules or tablets together with an excipient, and then, a coating layer is formed on the surface thereof. This is based on the concept that when a coating layer is formed under constant conditions on a particle having uniform size and shape, the coating layer displays a uniform properties. Therefore, by processing the drug to be coated into a granule or tablet, whose size and shape are easily controllable, the rate of release of the medicinal agent can be decreased.
In addition, when a coating layer is provided on the surface of a granule or a tablet containing a medicinal agent, it is desired that the particle size thereof is as small as possible. The reason for this is that when there is a defect in the coating layer on the surface of the granule or the tablet, or there is a variation in the properties of the coating layer among the granules or tablets, the more the number of granules or tablets to be dosed at one time, the smaller the influence caused by the defect or in the dosage for one time. Thus, the smaller the particle size of the granules or tablets, the higher the safety of the dosage form.
Moreover, the release of the medicinal agent from the granule or the tablet is related not only to physical processes in the coating layer, such as the diffusion of water and the medicinal agent through the coating layer, the dissolution of the coating layer itself and the like, but also to complicated physical processes within the granule or the tablet, such as the diffusion of water, the dissolution of the medicinal agent, the mixing of water with the dissolved medicinal agent, the diffusion of the solution of the medicinal agent and the like. Particularly, the larger the particle size of the granule or tablet, the larger the contribution of the latter processes to the release of the medicinal agent. Therefore, it is advantageous to provide a coating layer on the surface of a granule or a tablet having a small particle size in view of simplicity in analysis, and ease in designing dosage form and obtaining one showing a desired dissolution curve.
However, a special technique has been required in order to process a granule or tablet containing a medicinal agent to less than or equal to 100 .mu.m. particle size i.e. such as the technique using a ball mill, a colloid mill, a jet mill or the like. Further, it has been impossible to form a coating layer on the surface of such a small particle. As a result, particles having a diameter of more than 200 .mu.m, or at the smallest, more than 100 .mu.m. can be used under conventional technical conditions.
The present inventors developed a granulating-coating apparatus capable of providing a good coating layer on the surface of a small particle having a particle size of less than or equal to 100 .mu.m. Further, they showed that a dosage form obtained by coating material powder, i.e. particles before granulation, of a medicinal agent such as theophylline with a layer of wax using the above apparatus has a prolonged release effect (Abstracts of Oral presentations in Autumn Session of Society of Powder Technology, p.77, 1989; Japanese Patent Application Laid-open Nos. 1-176921 and 1-273337). However, no preferable prolonged release dosage form was obtained when only the above granulating-coating apparatus was used, since the prolonged release effect was not sufficient and its dissolution curve was a first-order dissolution curve.